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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

1415 - Pharmacodynamic (PD) changes in tumors and peripheral blood T cell receptor (TCR) repertoire in a phase I study combining OX40 (PF-04518600) and 4-1BB (utomilumab) agonistic monoclonal antibodies (mAbs)

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Topics

Clinical Research

Tumour Site

Presenters

Omid Hamid

Citation

Annals of Oncology (2018) 29 (suppl_8): viii400-viii441. 10.1093/annonc/mdy288

Authors

O. Hamid1, S. Hu-Lieskovan2, W. Ros3, A. Diab4, A.B. El-Khoueiry5, J.A. Thompson6, F.A. Eskens7, J. Spano8, E. Angevin9, N.A. Rizvi10, J.S. Wasser11, P.A. Ott12, A. Chiappori13, T. Joh14, H.I. Krupka14, S. Potluri14, X. Wang14, B.J. Ganguli14, J. Chou14, T. Doi15

Author affiliations

  • 1 Translational Research And Immunotherapy, The Angeles Clinic and Research Institute, 90025 - Los Angeles/US
  • 2 Medicine, UCLA School of Medicine, 90095 - Los Angeles/US
  • 3 Medical Oncology, Netherlands Cancer Institute, Amsterdam/NL
  • 4 Medical Oncology, MD Anderson Cancer Center, 77030-4095 - Houston/US
  • 5 Medical Oncology, USC/Norris Comprehensive Cancer Center, Los Angeles/US
  • 6 Medical Oncology, University of Washington Seattle Cancer Care Alliance, 98109 - Seattle/US
  • 7 Medical Oncology, Erasmus University Medical Center, 3015 CE - Rotterdam/NL
  • 8 Medical Oncology, Groupe Hospitalier Pitié Salpetriere, 75651 - Paris/FR
  • 9 Medical Oncology, Gustave Roussy Institut de Cancérologie, 94805 - Villejuif/FR
  • 10 Hematology And Oncology, Columbia University Medical Center College of Physicians & Surgeons, New York Presbyterian Hospital, 10032 - New York/US
  • 11 Hematology And Medical Oncology, University of Connecticut School of Medicine, Farmington/US
  • 12 Center For Immuno-oncology, Dana-Farber Cancer Institute, Boston/US
  • 13 Thoracic Oncology Program, H. Lee Moffitt Cancer Center University of South Florida, 33612 - Tampa/US
  • 14 Pfizer, Inc., New York/US
  • 15 Gastrointestinal Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
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Resources

Abstract 1415

Background

PF-04518600 (PF-8600) and utomilumab (uto) are human IgG2 agonistic mAbs against the tumor necrosis factor superfamily receptors OX40 and 4-1BB, respectively. Both receptors play key roles in T cell survival, proliferation, and activation. PF-8600 has been shown to increase proliferation and activation of peripheral CD4 memory T cells and uto has a similar effect on CD8 memory T cells. Previously, in patients treated with PF-8600, PD changes have been observed in tumor biopsy samples, including enrichment of gene sets associated with immune activation as well as CD4/8 T cell clonal expansion in peripheral blood. PD changes in tumors and peripheral TCR repertoire for PF-8600 + uto are reported here.

Methods

Paired biopsy samples at baseline and week 6 were collected from 5 dose cohorts (0.1/20, 0.3/20, 0.3/100, 1.0/100, 3.0/100; dose of PF-8600 in mg/kg / flat dose of uto in mg) during dose escalation. Biopsy tissues were analyzed by IHC and RNAseq to evaluate the PD effects of PF-8600 + uto. CD4, CD8, OX40, and FoxP3 expression was measured by IHC. Changes in transcriptional profile were measured by RNAseq analysis and gene ranking-based gene set enrichment analysis. CD4/8 cells were isolated from blood samples at the same time points. DNA was extracted and submitted for high-throughput sequencing of TCRβ.

Results

In an analysis of paired biopsy samples from dose cohorts including ≥ 0.3 mg/kg PF-8600, OX40 was among the genes that showed increased expression. The top gene sets exhibiting significant enrichment by RNAseq were associated with immune activation. TCR sequencing revealed clonal expansion of CD4/8 T cells at all dose levels.

Conclusions

Increases in immune-related markers including OX40 and enrichment of gene sets associated with immune activation were observed in tumor tissue, providing evidence of an active, immunomodulatory mechanism for PF-8600 + uto. Peripheral CD4/8 T cell populations exhibited clonal expansion at all dose levels, further suggesting an immune-activating PD effect. Further evaluation of PF-8600 + uto safety, efficacy, and PD continues in NSCLC and melanoma cohorts.

Clinical trial identification

NCT02315066.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Editorial Acknowledgement

Editorial support was provided by Engage Scientific Solutions, Southport, CT.

Disclosure

O. Hamid, S. Hu-Lieskovan, J.A. Thompson: Research funding: Pfizer. A.B. El-Khoueiry: Research funding: AstraZeneca and Astex; Consulting honoraria: BMS, Bayer, Eisai, CytomX, EMD Serono. J-P. Spano: Consulting honoraria: Pfizer. N.A. Rizvi: Consulting honoraria: Merck, AstraZeneca, Roche, BMS, Novartis, Pfizer, Lilly, Abbvie, Merck KGaA, Regeneron; Shareholder: Gritstone Oncology, ARMO Biosciences. J.S. Wasser: Research funding: Merck, Incyte, Pfizer, Guardent; Speakers bureau honoraria: Novartis; Consulting honoraria: Amgen; Equity ownership in Pfizer, Merck, Bristol-Meyers Squibb. P.A. Ott: Consulting or advisory role: Amgen, Bristol-Myers Squibb, Alexion, CytomX Therapeutics, Celldex, Genentech, Novartis, Pfizer, Neon Therapeutics; Speaking fees: Merck & Co., Inc.; Research funding to institution: Bristol-Myers Squibb, Merck & Co., Inc., Astra Zeneca/MedImmune, Celldex, Neon Therapeutics, Pfizer, CytomX, and ARMO BioSciences. A. Chiappori: Research funding: AstraZeneca, BMS, Novartis; Consulting/speakers’ bureau honoraria: AstraZeneca, Boehringer, Celgene, Genentech, Merck, Novartis, Takeda. T. Joh, H.I. Krupka, S. Potluri, X. Wang, B.J. Ganguli, J. Chou: Employee: Pfizer at the time of this study. All other authors have declared no conflicts of interest.

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